Respiratory syncytial virus (RSV) is the most common cause of pneumonia and bronchiolitis in infancy. After an episode of RSV bronchiolitis severe enough to require hospitalization, 20-40% of infants develop asthma. In older children who already have asthma, an acute infection with RSV commonly causes an exacerbation of symptoms. Our goal is to establish the sheep as an animal model of RSV bronchiolitis in order to understand i) the mechanism for the varying severity of clinical respiratory disease, and ii) the relationship between RSV and airway reactivity. The advantages of using sheep as a model of RSV bronchiolitis are: i) RSV infection in sheep resembles that of infants as lambs develop broncholitis on exposure to RSV whereas other species develop an upper respiratory tract infection or pneumonitis, and ii) detailed serial measurements of lung mechanisms and airway reactivity can be made in the unanesthetized sheep. First, the effect of age at the time of inoculation will be assessed. Three age groups will be studied: i) colostrum-fed 1 week old lambs, ii) lambs whose level of maternally-acquired antibody to RSV has reached a minimum, and iii) seronegative adult sheep. Animals will be given aerosolized ovine RSV via an endotracheal tube and the response assessed by physical examination, serum for antibody titer, T-cell activation, lung lavage for viral quantitation, lung mechanics, arterial blood gases, and lung histology. Also the effect of dose of virus and route of administration (aerosol, intranasal or intratracheal) on disease severity will be determined. Next, the severity of RSV infection will be enhanced by vaccinating lambs with a formalin-inactivated RSV vaccine. (This type of vaccine causes enhanced disease in children, cotton rats, and cattle.) Airway reactivity to aerosol bronchoconstrictors (histamine, carbachol and citric acid) will be measured in both vaccinated and unvaccinated RSV infected animals. Further experiments will depend on results from this intitial work. Possibilities include i) passive transfer of antibody to determine the role of humoral immunity in enhanced disease and/or increased airway reactivity, ii) lung tissue culture of animals at different ages to determine the mechanism of age susceptibility, or iii) characterizing the increase in airway reactivity (time course and smooth muscle receptor function).